Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal. In instances where the triggering allergen is not known, establishing the cause of anaphylaxis is pivotal to long-term risk management. Determining the etiology is limited, however, to known causes of anaphylaxis. Therefore, identification of novel causative agents will provide an important step forward by reducing risk of disease and facilitating new, specific treatment approaches. The overarching hypothesis for this proposal is that IgE antibodies to carbohydrates are a major factor in anaphylaxis that currently appears to be idiopathic. We have recently identified and described a carbohydrate, alpha-gal, as a novel food allergen. Patients who have IgE antibodies to alpha-gal report delayed anaphylaxis or urticaria occurring 3-6 hours after eating beef, pork or lamb. By understanding the factors that control this reaction and contribute to the delay, the proposed research will provide insight into the factors that control anaphylaxis and advance the field of food allergy. A delay of 3-6 hours is most unusual in patients with classical food allergy and warrants investigation of the mechanism(s) involved. Using ex-vivo histamine release and basophil activation studies, we will determine whether IgE to alpha-gal can produce activation of these cells. Most patients who have IgE to alpha-gal tolerated mammalian meat for many years. Interestingly, greater than 90% of patients in our cohort who have IgE to alpha-gal report being bitten by large numbers of adult or larval ticks ('seed ticks') in the weeks or months prior to developing symptoms. Hence, these bites may serve as the inciting event in the development of IgE antibodies to alpha-gal and potentially other carbohydrates. Our current work has shown that IgE to the carbohydrate alpha-gal is present in a cohort of patients who report delayed anaphylaxis and allergic reactions after eating mammalian meat. We believe that IgE to alpha-gal and other carbohydrates represents a novel cause of food allergy. The specific aims outlined in this proposal are designed to more accurately define the clinical histories associated with IgE to alpha-gal, elucidate the functional role of this IgE in food allergy and investigate the cause of the delay in symptoms (Specific Aim 1). Specific Aim 2 focuses on the role of ticks in initiating the production of IgE to alpha-gal through establishing the epidemiology of the IgE antibody response to alpha-gal, developing assays for IgE antibodies to tick antigens other than alpha-gal and using animal models to study the IgE antibody response to ticks. Anaphylaxis, or shock, is a severe allergic reaction that can progress quickly and may be fatal if appropriate medical action is not taken. We have identified a group of patients in the Southeastern U.S. who, after being bitten by ticks or chiggers, develop delayed anaphylaxis 3-6 hours after eating beef, pork or lamb and appear to be allergic to a sugar on red meat. Because of the delay, their symptoms would normally be regarded as 'spontaneous'or 'of unknown cause'but understanding why the delay occurs and why adult patients in the Southeast are suddenly becoming allergic to red meat may provide real insight into the factors that control anaphylaxis and food allergy.